MicroRNA-directed modulation of intraocular pressure

Summary

Principal Investigator: Benjamin R tenOever
Abstract: DESCRIPTION (provided by applicant): Lowering intraocular pressure (IOP) slows or stops the loss of vision in primary open-angle glaucoma (POAG) patients, including in those with normal IOP. Unfortunately, current medical treatments are usually inadequate and do not target the conventional outflow pathway;the main route of aqueous humor egress and the site of extra resistance in POAG patients with elevated IOP. Presently in clinical trials are two new classes of drugs that inhibit the contractile machinery of conventional outflow pathway cells, effectively lowering IOP. Although promising, such drugs have limitations: they are disruptive, non-specific, do not restore tissue function, and are dependent on patient compliance for daily administration. An attractive therapeutic alternative for POAG are molecular therapeutics such as microRNAs (miRNAs) that achieve prolonged modulation of various biological functions such as cell contractility because of their ability to regulate entire networks of genes. Our group has recently identified miR-200c as a strong candidate to control IOP based on its ability to inhibit contractio of trabecular meshwork cells and lower IOP in vivo. To improve delivery of miRNAs in vivo, we have developed a new class of viral vectors, including influenza-associated-virus viral-like-particles (IAV-VLP) that overcome the limitation for effective in vivo delivery of miRNAs that result from overloading of the miRNA biogenesis components. Thus, we hypothesize that miR-200c regulates conventional outflow via modification of contractile state of trabecular and/or Schlemm's canal cells. We also hypothesize that over expression of miR-200c using IAV- VLP decreases IOP in normotensive animals and prevents the pathologic increase in IOP in experimental models of glaucoma. To test our hypothesis we have constructed three specific aims designed to (i) Assess the role of miR-200c on the regulation of cellular contractility of HTM and SC cells;(ii) Examine the effects of miR-200c on aqueous humor outflow function and IOP in perfused human anterior segments and living rat eyes;(iii) Test whether increased expression of miR-200c in the cells of the outflow pathway can prevent or restore the increase in IOP in experimental models of glaucoma. Taken together, results obtained from these investigations will establish feasibility of miRNA therapy for ocular hypertension in glaucoma, optimize delivery of miRNAs to conventional outflow tissues, identify new genes regulated by miRNA-200c responsible for IOP lowering and generate novel animal models for studying glaucoma.
Funding Period: 2013-04-01 - 2017-03-31
more information: NIH RePORT

Top Publications

  1. pmc Scleral micro-RNA signatures in adult and fetal eyes
    Ravikanth Metlapally
    School of Optometry, University of California, Berkeley, California, United States of America
    PLoS ONE 8:e78984. 2013
  2. pmc A versatile RNA vector for delivery of coding and noncoding RNAs
    Sonja Schmid
    Dept of Microbiology at the Icahn School of Medicine at Mount Sinai, New York, New York, USA
    J Virol 88:2333-6. 2014
  3. pmc Role of microRNAs in the trabecular meshwork
    Pedro Gonzalez
    Department of Ophthalmology, Duke University, Durham, North Carolina
    J Ocul Pharmacol Ther 30:128-37. 2014

Detail Information

Publications3

  1. pmc Scleral micro-RNA signatures in adult and fetal eyes
    Ravikanth Metlapally
    School of Optometry, University of California, Berkeley, California, United States of America
    PLoS ONE 8:e78984. 2013
    ..In this study, the scleral micro-RNA expression profile of rapidly growing human fetal eyes was compared with that of stable adult donor eyes using high-throughput microarray and quantitative PCR analyses...
  2. pmc A versatile RNA vector for delivery of coding and noncoding RNAs
    Sonja Schmid
    Dept of Microbiology at the Icahn School of Medicine at Mount Sinai, New York, New York, USA
    J Virol 88:2333-6. 2014
    ..Here we illustrate that a self-replicating, noninfectious RNA, modeled on influenza virus, provides one such example of a versatile in vivo delivery system for silencing and/or expressing a desired RNA for therapeutic purposes. ..
  3. pmc Role of microRNAs in the trabecular meshwork
    Pedro Gonzalez
    Department of Ophthalmology, Duke University, Durham, North Carolina
    J Ocul Pharmacol Ther 30:128-37. 2014
    ....

Research Grants30

  1. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
    ..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..
  2. eNOS-Dependent Mechanoregulation of Intraocular Pressure
    W Daniel Stamer; Fiscal Year: 2013
    ..abstract_text> ..
  3. Role of endothelin receptors in glaucomatous optic neuropathy
    Raghu R Krishnamoorthy; Fiscal Year: 2013
    ..The information gained from this study could be useful in developing endothelin receptor antagonists as neuroprotective agents in glaucoma treatment. ..
  4. Glucocorticoids, ocular hypertension, and glaucoma
    Thomas Yorio; Fiscal Year: 2013
    ....
  5. Mechanisms of Aqueous Humor Homeostasis -- Role of Monocytes
    Jorge A Alvarado; Fiscal Year: 2013
    ..Therefore, subsequent studies would translate our theoretical model into clinically relevant approaches for glaucoma treatments, and including cytokine-based or cell-based treatment modalities. ..
  6. Trabecular Meshwork Cytoskeletal Signaling-Regulation of Aqueous Humor Outflow
    P Vasantha Rao; Fiscal Year: 2013
    ....
  7. Interleukin-6 and Retinal Ganglion Cell Degeneration in Glaucoma
    Rebecca M Sappington; Fiscal Year: 2013
    ..We propose a series of studies to examine the potential of the inflammatory cytokine interleukin-6 as a therapeutic target to rescue RGCs in glaucoma. ..